Prostaglandins (PGs) which belong to the prostanoids family are known to have diverse biological activities such as contraction and relaxation of smooth muscle, inhibition and enhancement of neurotransmitter release, inflammation, including pain and bone metabolism (Coleman et al. 1989; EP1114816).
In particular, Prostaglandin E2 (PGE2) which is the naturally-occurring agonist of EP receptor, was found to have various roles in ovulation and fertilization, in the control of blood pressure, febrile responses, regulation of bicarbonate secretion induced by acid-stimulation in the duodenum, bone resorption, smooth muscle contraction regulation, TNF down-regulation and inhibition of microglial IL-12 secretion (Ushikibi et al., 2000; Miyaura. et al., 2001, Nippon Yakurigaku Zasshi, 117(4): 293-7; Benoit et al., 2002 and Levi et al., 1998 Biochimie 80(11):899-904)
The EP receptor has been further classified into four different receptor subtypes: EP1, EP2, EP3, and EP4 (Coleman et al. 1994).
Knock-out mice lacking each sub-type of the EP receptor gave evidence of the different roles played by these receptors (Ushikubi et al., 2000) in various mechanisms such as ovulation (EP2), blood pressure control (EP2), closure of ductus arteriosus (EP4) and bone resorption (EP4) (Miyaura et al., 2001).
As prostaglandin E2 (PGE2) is a natural ligand for all sub-types of the EP receptor, selective effects on one of the sub-types of the EP receptor is impossible to achieve with the endogenous prostaglandins.
Several prostanoid receptors and modulators of those receptors have been reported with different range of selectivity for the various receptor sub-types (Coleman et al. 1994, Abramowitz et al., 2000, and Benoit et al., 2002).
Recently, EP2 agonists have been developed (U.S. Pat. No. 6,235,780 and WO 9933794). The combination of an EP2 agonists in combination of an EP4 agonist has been developed for osteoporosis treatment (US 20010056060). EP4 selective agonists have been developed for the treatment of bone disorders (WO 0242268 and WO 0146140), erectile dysfunction (WO 9902164) and other prostaglandin related disorders (WO 0224647, US 20020004495, WO 0003980, WO 03007941 and WO 03008377). EP2 and EP4 antagonists have been also reported (Benoit et al., 2002).